Table 5.

Recent studies on extracellular vesicles to breach the blood-brain barrier for central nervous system disorders.

Surface modify	Targeting ligands	Receptors	Model drug	Use	Others	Refs
CpG-exosomes -TanIIA-GL nanomicelles (CpG-EXO/TGM)	Tf	TfR	Tanshinone IIA; Glycyrrhizic acid; CpG oligonucleotides	GBM	In this study, a TGM was constructed, and the TGM was then loaded into serum EXO to form CpG-EXO/TGM. CpG-EXO/TGM can effectively prevent postoperative recurrence by using chemotherapy and immunotherapy in the treatment of GBM.	[107]
macrophage-derived exosomes loaded with curcumin (EXO-Cur)	/	/	Cur	I/R	EXO-Cur has inflammation-related targeting properties. EXO-Cur has a neuroprotective effect by eliminating ROS generation, reducing mitochondria-mediated apoptosis, and alleviating the damage of BBB caused by cerebral ischemia.	[279]
cEM@DEP-siRNA	/	/	Panobinostat; PPM1D-siRNA	glioma	cEM@DEP-siRNA is a nano drug delivery system based on functionalized macrophage EXO with panobinostat and PPM1D‐siRNA.	[280]
magnetic nanoparticles@ brequinar@A2-EXO- siGPX4 (MNP@BQR@A2-EXO-siGPX4)	A2	LRP1	GPX4 SiRNA; brequinar	GBM	MNP@BQR@A2-EXO-siGPX4 enhances ferroptosis synergistically to treat GBM by disintegrating the DHODH and GPX4 ferroptosis defense axes.	[220]
EXO-metformin/sicPLA2	Tf	TfR	Metformin; sicPLA2	glioma	EXO-metformin/sicPLA2 impairment Mitochondrial energy metabolism in GBM.	[281]
(CSI@EXO-AS1411; CSI: catalase @SiO2- catalase	/	/	catalase	GBM	CSI@Ex-A has efficient BBB penetration, good cancer cell targeting, good biocompatibility, and long circulation time.	[277]
Neutrophils (NEs)-EXO/DOX	/	/	DOX	glioma	In vivo zebrafish and glioma mouse models showed that NEs-EXO/DOX rapidly penetrated the BBB and migrated to the brain. In addition, NEs-EXO/DOX can respond chemoattractively to inflammatory stimuli. Intravenous administration of NEs-EXO/DOX effectively inhibited tumor growth and prolonged survival.	[282]
exosome coated DOX-loaded nanoparticles	/	/	DOX	GBM	Exosome coated DOX-loaded nanoparticles have great potential to penetrate the blood-brain barrier and induce tumor cell apoptosis and ICD, as well as survival in tumor-bearing GBM mice.	[278]
a dual-receptor-specific exosome loaded with TMZ and BG (termed as EXO-An2-Apt-TMZ and EXO-An2-Apt-BG)	A2; CD133 RNA aptamers (Apt)	LRP1; CD133	TMZ; O6-benzylguanine (BG)	GBM	After intravenous injection of EXO-An2-Apt-TMZ and EXO-An2-Apt-BG, due to the synergistic effect of An2 and Apt, the nanocomposites could cross the BBB and actively reach GBM cells and GSC, exerting the corresponding efficacy of TMZ and BG.	[283]
DTX@A2- exosomes-mimetics (EM)	A2	LRP1	DTX	GBM	DTX@A2-EM showed significant inhibitory effect on GBM growth in situ and reduced the side effects of chemotherapy drugs.	[284]
HSSP-BMSCEXO-TMZ; HSSP-BMSCEXO-SiRNA	HMOX1 targeting ligand	HMOX1	TMZ; STAT3 SiRNA	GBM	The multifunctional NNPS can cross the BBB and target GBM cells, and the synergistic effect between TMZ released by the NPS and SiSTAT3 can restore TMZ sensitivity of TMZresistant glioma for TMZ chemotherapy.	[285]
ExoP -Bryostatin-1 (Bryo)	the ligand of platelet-derived growth factor receptor α (PDGFRα)	PDGFRα	Bryo	MS	ExoP means that EXO is derived from NSC expressing PDGFRα ligands.	[286]
brain microvascular endothelial cells (HBMVECs) derived exosomes (HBMVECs-Ex)	/	/	P-glycoprotein	AD	HBMVECs-Ex, which has inherited P-glycoprotein from its parent cells, functions to promote P-glycoprotein-mediated Aβ clearance under AD conditions.	[287]
DOX and PTX-loaded EXO	/	/	DOX; PTX	glioma	Microfluidics assisted DOX and PTX loading into EXO.	[288]
reassembly-exosomes (R-EXO)-TMZ/DHT	/	/	TMZ; Dihydrotanshinone (DHT)	glioma	R-EXO-TMZ/DHT can target glioma cells by virtue of its natural homologous targeting ability. DHT can effectively overcome the drug resistance induced by TMZ and has a good therapeutic effect on glioma.	[289]
MicroRNA loaded CXCR4 mpEV	CXCL12	CXCR4	miRNA-100; Cy5-AmiRNA-21	GBM	They used the ID method to deliver microRNA-loaded CXCR4 mpEV into the brain, release the carried miRNA-100 and Cy5-AmiRNA-21 to improve the sensitivity of GBM cells to TMZ, inhibit tumor growth, and improve the overall survival of model mice.	[290]
atorvastatin-loaded hEnMSCs exosomes	/	/	atorvastatin	GBM	hEnMSCs EXO are derived from human endometrial mesenchymal stem cells.	[291]
EXO-Silibinin (Slb)	/	/	Slb	AD	Slb has dual effects of reducing Aβ aggregation by binding to Aβ monomers and inhibiting astrocyte activation, which favors its neuroprotective effect as A treatment for AD.	[292]
anti‐microRNA‐21 oligonucleotides (AMO21c)-T7 peptides -cell membrane nanovesicles (AMO21c-T7-CMNVs)	cholesterol-linked T7 peptides	TfR	AMO21c	GBM	Delivery of AMO21c to the brain was more effective in T7 modified CMNV than in CMNV.	[293]
curcumin loaded human endometrial stem cells derived exosomes (hEnSCs EXOs-Cur)	/	/	Cur	PD	hEnSCs EXOs-Cur crossed the BBB by increasing BCL2 expression level as well as reducing BAX and caspase-3, enhanced enhanced motor incongruency movement, inhibited αS protein aggregation and rescued neuronal cell death.	[294]
NSC-EXOs loaded with miR-124-3p	/	/	small molecule miR-124-3p	glioma	NSC-EXO loaded with miR-124-3p significantly inhibited the proliferation, invasion and migration of glioma cells.	[295]
EXO-miR-1208	/	/	miR-1208	glioma	After FUS irradiation, Exo-Mir-1208 improved the ability to penetrate the BBB, promoted the uptake of miR-1208 in EXO by glioma cells, and effectively inhibited glioma.	[296]
T7-siYY1-exo	T7	TfR	SiYY1	GBM	7-siYY1-exo can enhance the sensitivity to chemoradiotherapy and reverse drug resistance. In addition, T7-siYY1-exo and TMZ/Irradiation exerted a synergistic anti-GBM effect and significantly improved the survival time of GBM mice.	[297]
atorvastatin (Ato) loaded EXOs (AtoEXOs)	/	/	atorvastatin	GBM	EXO is derived from human endometrial stem cells.	[298]